tbuckley/cabot-search huggingface dataset:
Progressively Enhancing Stemness of Adoptively Transferred T Cells with PI3Kδ Blockade Improves Metabolism and Antitumor Immunity
Authors: Guillermo O. Rangel Rivera, Connor J. Dwyer, Hannah M. Knochelmann, Aubrey S. Smith, Bülent Arman Aksoy, Anna C. Cole, Megan M. Wyatt, Soundharya Kumaresan, Jessica E. Thaxton, Gregory B. Lesinski, Chrystal M. Paulos
Journal: Cancer Research (2023)

Abstract Generating stem-like memory T cells (TSCM) is a potential strategy to improve adoptive immunotherapy. Elucidating optimal ways to modulate signaling pathways that enrich TSCM properties could identify approaches to achieve this goal. We discovered herein that blocking the PI3Kδ pathway pharmaceutically to varying degrees can generate T cells with increasingly heightened stemness properties, based on the progressive enrichment of the transcription factors Tcf1 and Lef1. T cells with enhanced stemness features exhibited metabolic plasticity, marked by improved mitochondrial function and glucose uptake after tumor recognition. Conversely, T cells with low or medium stemness were less metabolically dynamic, vulnerable to antigen-induced cell death, and expressed more inhibitory checkpoint receptors. Only T-cell receptor–specific or chimeric antigen receptor (CAR)-specific T cells with high stemness persisted in vivo and mounted protective immunity to tumors. Likewise, the strongest level of PI3Kδ blockade in vitro generated human tumor-infiltrating lymphocytes and CAR T cells with elevated stemness properties, in turn bolstering their capacity to regress human solid tumors. The stemness level of T cells in vitro was important, ultimately impacting their efficacy in mice bearing three distinct solid tumors. Lef1 and Tcf1 sustained antitumor protection by donor high CD8+ TSCM or CD4+ Th17SCM, as deletion of either one compromised the therapeutic efficacy. Collectively, these findings highlight the importance of strategic modulation of PI3Kδ signaling in T cells to induce stemness and lasting protective responses to solid tumors. Significance: Elevating T-cell stemness by progressively blocking PI3Kδ signaling during ex vivo manufacturing of adoptive cell therapies alters metabolic and functional properties to enhance antitumor immunity dependent on Tcf1 and Lef1.
Uptake of 68Ga-PSMA in Avascular Necrosis of the Femoral Head in a Patient With Prostate Cancer
Authors: Berna Okudan, Bedri Seven, Haluk Sayan
Journal: Clinical Nuclear Medicine (2023)

A 69-year-old man with prostate cancer treated with radical prostatectomy underwent 68 Ga-PSMA PET/CT due to biochemical recurrence. Increased radiotracer uptake in the prostate bed suggestive of local recurrence was detected. The right hip also displayed increased 68 Ga-PSMA activity, which was consistent with the avascular necrosis findings on MRI.
Noninvasive assessment of hepatic decompensation
Authors: Maja Thiele, Stine Johansen, Mads Israelsen, Jonel Trebicka, Juan G. Abraldes, Pere Gines, Aleksander Krag
Journal: Hepatology (2023)

Noninvasive tests (NITs) are used in all aspects of liver disease management. Their most prominent break-through since the millennium has been in advancing early detection of liver fibrosis, but their use is not limited to this. In contrast to the symptom-driven assessment of decompensation in patients with cirrhosis, NITs provide not only opportunities for earlier diagnoses but also accurate prognostication, targeted treatment decisions, and a means of monitoring disease. NITs can inform disease management and decision-making based on validated cutoffs and standardized interpretations as a valuable supplement to clinical acumen. The Baveno VI and VII consensus meetings resulted in tangible improvements to pathways of care for patients with compensated and decompensated advanced chronic liver disease, including the combination of platelet count and transient elastography to diagnose clinically significant portal hypertension. Furthermore, circulating NITs will play increasingly important roles in assessing the response to interventions against ascites, variceal bleeding, HE, acute kidney injury, and infections. However, due to NITs’ wide availability, there is a risk of inaccurate use, leading to a waste of resources and flawed decisions. In this review, we describe the uses and pitfalls of NITs for hepatic decompensation, from risk stratification in primary care to treatment decisions in outpatient clinics, as well as for the in-hospital management of patients with acute-on-chronic liver failure. We summarize which NITs to use when, for what indications, and how to maximize the potential of NITs for improved patient management.
Abnormal Cerebral FDG Accumulation in Acute Intracerebral and Subarachnoid Hemorrhages Due to Different Mechanisms
Authors: Tsz-Kit Chow, Ka-Lun Chiu, Chun-Ho Chan, Wai-Han Ma
Journal: Clinical Nuclear Medicine (2023)

Changes in cerebral glucose metabolism after acute intracranial hemorrhage have been rarely described. We present a patient with abnormal cerebral FDG accumulation in acute intracerebral and subarachnoid hemorrhages due to different mechanisms on FDG PET/CT. The patient received conservative management and died 2 months later. This case demonstrated the different mechanisms of cerebral FDG accumulation in different types of intracranial hemorrhage, which may be helpful for future research to optimize patient care.
Hyperphosphatemia-Related False-Positive 99mTc-Pyrophosphate Myocardial Scan: A Case Report With Endomyocardial Biopsy Result
Authors: Lien-Hsin Hu, Yu Kuo, Fu-Pang Chang, Wei-Ting Wang, Bang-Hung Yang, Wen-Sheng Huang, Yuh-Feng Wang
Journal: Clinical Nuclear Medicine (2023)

With documented high specificity, 99m Tc-pyrophosphate (PYP) scan enables the diagnosis of transthyretin cardiomyopathy to be made reliably without endomyocardial biopsy in patients who do not have monoclonal gammopathy. We report a case with extensive myocardial uptake of Perugini 3 score in the 3-hour 99m Tc-PYP myocardial SPECT that suggested transthyretin cardiac amyloidosis. However, a followed endomyocardial biopsy revealed no amyloid deposition. In this case, hyperphosphatemia was the most likely and presumptive cause of the false-positive 99m Tc-PYP scan. With this case, our experiences of the potential causes of false-positive results of 99m Tc-PYP are further expanded.
Targeting Transcriptional Regulation with a CDK9 Inhibitor Suppresses Growth of Endocrine- and Palbociclib-Resistant ER+ Breast Cancers
Authors: Arany Soosainathan, Marjan Iravani, Rania El-Botty, John Alexander, Laura Sourd, Ludivine Morisset, Pierre Painsec, Rebecca Orha, Joanna Nikitorowicz-Buniak, Sunil Pancholi, Syed Haider, Mitch Dowsett, Elisabetta Marangoni, Lesley-Ann Martin, Clare M. Isacke
Journal: Cancer Research (2023)

The combination of endocrine therapy and CDK4/6 inhibitors such as palbociclib is an effective and well-tolerated treatment for estrogen receptor-positive (ER+) breast cancer, yet many patients relapse with therapy-resistant disease. Determining the mechanisms underlying endocrine therapy resistance is limited by the lack of ability to fully recapitulate inter- and intratumor heterogeneity in vitro and of availability of tumor samples from women with disease progression or relapse. In this study, multiple cell line models of resistant disease were used for both two-dimensional (2D)- and three-dimensional (3D)-based inhibitor screening. The screens confirmed the previously reported role of pro-proliferative pathways, such as PI3K-AKT-mTOR, in endocrine therapy resistance and additionally identified the transcription-associated cyclin-dependent kinase CDK9 as a common hit in ER+ cell lines and patient-derived organoids modeling endocrine therapy-resistant disease in both the palbociclib-sensitive and palbociclib-resistant settings. The CDK9 inhibitor, AZD4573, currently in clinical trials for hematologic malignancies, acted synergistically with palbociclib in these ER+in vitro 2D and 3D models. In addition, in two independent endocrine- and palbociclib-resistance patient-derived xenografts, treatment with AZD4573 in combination with palbociclib and fulvestrant resulted in tumor regression. Tumor transcriptional profiling identified a set of transcriptional and cell-cycle regulators differentially downregulated only in combination-treated tumors. Together, these findings identify a clinically tractable combination strategy for overcoming resistance to endocrine therapy and CDK4/6 inhibitors in breast cancer and provide insight into the potential mechanism of drug efficacy in targeting treatment-resistant disease.
Extraosseous Uptake and Multiple Metastases of Splenic Composite Hemangioendothelioma on 99mTc-MDP Scintigraphy
Authors: Wenpeng Huang, Yuhan Zhou, Qi Yang, Liming Li, Lei Kang
Journal: Clinical Nuclear Medicine (2023)

Abstract Composite hemangioendothelioma is a rare disease that exhibits biological potency ranging from benign to low-grade malignancy, and hepatic and bone metastases are even rarer. Here, we present the imaging findings of a 65-year-old man with splenic composite hemangioendothelioma and multiple metastases. A bone scan revealed abnormal uptake of 99m Tc-MDP in multiple bones and spleen, whereas enhanced CT demonstrated splenic lesions with low density and mild enhancement. Based on pathological examination, the patient was diagnosed with splenic composite hemangioendothelioma with bone metastasis.
Multiomics tools for improved atherosclerotic cardiovascular disease management
Authors: Miron Sopic, Baiba Vilne, Eva Gerdts, Fábio Trindade, Shizuka Uchida, Soliman Khatib, Stephanie Bezzina Wettinger, Yvan Devaux, Paolo Magni
Journal: Trends in Molecular Medicine (2023)

Multiomics studies offer accurate preventive and therapeutic strategies for atherosclerotic cardiovascular disease (ASCVD) beyond traditional risk factors. By using artificial intelligence (AI) and machine learning (ML) approaches, it is possible to integrate multiple 'omics and clinical data sets into tools that can be utilized for the development of personalized diagnostic and therapeutic approaches. However, currently multiple challenges in data quality, integration, and privacy still need to be addressed. In this opinion, we emphasize that joined efforts, exemplified by the AtheroNET COST Action, have a pivotal role in overcoming the challenges to advance multiomics approaches in ASCVD research, with the aim to foster more precise and effective patient care.
Clonal evolution dissection reveals that a high MSI2 level promotes chemoresistance in T-cell acute lymphoblastic leukemia
Authors: Jingliao Zhang, Yongjuan Duan, Peng Wu, Yanxia Chang, Yue Wang, Tianyuan Hu, Chao Liu, Xiaoyan Chen, Suyu Zong, Xiaoli Chen, Yangping Wu, Linlin Jin, Yang Lan, Xiaoming Liu, Xuelian Cheng, Feng Ding, Tianyu Li, Xiaojuan Chen, Ye Guo, Yumei Chen, Wenyu Yang, Li Zhang, Yao Zou, Tao Cheng, Xiaofan Zhu, Yingchi Zhang
Journal: Blood (2023)
Novel technique using metal clip and dental floss facilitates difficult biliary cannulation in Billroth II gastrectomy
Authors: Zhichu Qin, Jianlong He, Zhihe Deng, Yan Qin, Junlian He, Fenhua Ye, Lihao Wu
Journal: Endoscopy (2023)

We report the case of a 79-year-old woman with a previous Billroth II gastrectomy for gastric cancer who presented with jaundice (total bilirubin 120.72 mg/dL, direct bilirubin 96.3 mg/dL) and abdominal pain. Magnetic resonance pancreaticobiliary imaging demonstrated extrahepatic bile duct dilation and a distal common bile duct (CBD) stone (1.2 × 1 cm). Endoscopic retrograde cholangiopancreatography in patients with Billroth II anatomy is associated with low success rates of selective access to the afferent loop and cannulation of the CBD owing to the inverted position, as well as a high incidence of complications [1] [2]. For the current case, a forward-viewing colonoscope with a clear cap was chosen over a duodenoscope to decrease the difficulty of entry and limit potential adverse events, such as perforation [3].
A transnasal traction method using a novel traction device in pharyngeal endoscopic submucosal dissection
Authors: Yuhei Umeda, Yasuhiko Hamada, Yohei Ikenoyama, Hiroki Yukimoto, Misaki Nakamura, Noriyuki Horiki, Hayato Nakagawa
Journal: Endoscopy (2023)

Pharyngeal endoscopic submucosal dissection (ESD) is technically challenging because of the narrow and complex space involved in endoscopic maneuverability. Thus, the traction technique is important for completing the procedure. The transnasal endoscope method or transoral forceps method was useful for creating good countertraction during pharyngeal ESD [1] [2]. However, the former method requires another endoscope, and the latter method may interfere with the transoral endoscopic maneuver. The EndoTrac (Top Corporation, Tokyo, Japan) can improve the submucosal layer's visibility by changing the traction direction during ESD ([Fig. 1]) [3] [4] [5].
Endoscopic closure of a refractory urethroanal fistula using an innovative wound closure device
Authors: Pierre Lafeuille, Jérôme Rivory, Alexandru Lupu, Elena de Cristofaro, Jean-Christophe Saurin, Florian Rostain, Mathieu Pioche
Journal: Endoscopy (2023)

Gastrointestinal (GI) fistula is a rare chronic disease that affects the quality of life of patients and represents a real therapeutic challenge, with frequent recurrences [1]. Endoscopic management of GI fistulas combines both endoscopic submucosal dissection (ESD) and mechanical closure of the orifice [2]. We recently reported that the strategy of fistula endoscopic submucosal dissection with clip closure (FESDC) is effective and safe for permanent closure of GI fistulas [3], including in the exceptional cases where an aortoesophageal fistula has occurred [4]. In the case of anal fistulas, mechanical closure remains the greatest challenge because of the proximity of the anal sphincter, which does not allow effective closure using standard or over-the-scope clips.
Endoscopic submucosal dissection of esophageal squamous cell carcinoma with superficial capillary changes and epithelialization after chemotherapy for pancreatic adenocarcinoma
Authors: Alexandru Lupu, Sebastien Reynard, Jérôme Rivory, Pierre Lafeuille, Jean Grimaldi, Clara Yzet, Mathieu Pioche
Journal: Endoscopy (2023)

We present the case of a 79-year-old patient who was referred to us for endoscopic ultrasound evaluation of a cephalic pancreatic mass. He had a personal history of total laryngectomy for a T4 malignant tumor of the piriform sinus, with postoperative radiotherapy that ended 3 years previously. A phonatory cannula was in place from that moment on.
Endoscopic submucosal dissection using a novel therapeutic thin gastroscope for a locally recurrent rectal tumor after endoluminal rectal surgery
Authors: Yusaku Takatori, Noriko Matsuura, Atsushi Nakayama, Motohiko Kato, Naohisa Yahagi
Journal: Endoscopy (2023)

The lower rectum is the part of the gastrointestinal tract that gains most benefit from minimally invasive treatment such as endoscopic resection, because invasive surgery results in such a significant decrease in quality of life [1]. However, endoscopic resection in the lower rectum is sometimes technically difficult due to the narrow lumen and steep angle of the rectal wall. Here, we report the first description of endoscopic resection in the lower rectum using a novel thin therapeutic gastroscope.
A new treatment method for patients with cancer that cannot be resected en bloc by endoscopic submucosal dissection: the monorail method with clip-line traction
Authors: Masashi Ono, Ai Fujimoto, Kazuhisa Yamaguchi, Takahito Toba, Takahisa Matsuda
Journal: Endoscopy (2023)

Endoscopic submucosal dissection (ESD) is a safe endoscopic treatment for early-stage cancer of the esophagus, stomach, duodenum, and colon [1]. However, there are some cases in which ESD is difficult to resect en bloc owing to the location and extent of the lesion, fibrosis, and postoperative effects of the procedure. For these difficult cases, ESD may cause perforation, making en bloc resection difficult, and there are reports of treatment methods using various traction devices [2] [3]. The method presented here is to pull the lesion with a clip line, and then pass the thread through a snare from outside the intestinal tract to reach the lesion like a monorail.
Collagen fibril-like injectable hydrogels from self-assembled nanoparticles for promoting wound healing
Authors: Shanshan Li, Xiaoyun Li, Yidi Xu, Chaoran Fan, Zhong Alan Li, Lu Zheng, Bichong Luo, Zhi-Peng Li, Baofeng Lin, Zhen-Gang Zha, Huan-Tian Zhang, Xiaoying Wang
Journal: Bioactive Materials (2023)

Soft hydrogels are excellent candidate materials for repairing various tissue defects, yet the mechanical strength, anti-swelling properties, and biocompatibility of many soft hydrogels need to be improved. Herein, inspired by the nanostructure of collagen fibrils, we developed a strategy toward achieving a soft but tough, anti-swelling nanofibrillar hydrogel by combining the self-assembly and chemical crosslinking of nanoparticles. Specifically, the collagen fibril-like injectable hydrogel was subtly designed and fabricated by self-assembling methylacrylyl hydroxypropyl chitosan (HM) with laponite (LAP) to form nanoparticles, followed by the inter-nanoparticle bonding through photo-crosslinking. The assembly mechanism of nanoparticles was elucidated by both experimental and simulation techniques. Due to the unique structure of the crosslinked nanoparticles, the nanocomposite hydrogels exhibited low stiffness (G'< 2 kPa), high compressive strength (709 kPa), and anti-swelling (swelling ratio of 1.07 in PBS) properties. Additionally, by harnessing the photo-crosslinking ability of the nanoparticles, the nanocomposite hydrogels were processed as microgels, which can be three-dimensionally (3D) printed into complex shapes. Furthermore, we demonstrated that these nanocomposite hydrogels are highly biocompatible, biodegradability, and can effectively promote fibroblast migration and accelerate blood vessel formation during wound healing. This work presents a promising approach to develop biomimetic, nanofibrillar soft hydrogels for regenerative medicine applications.
TCF-1 limits intraepithelial lymphocyte antitumor immunity in colorectal carcinoma
Authors: Marina H. Yakou, Sonia Ghilas, Kelly Tran, Yang Liao, Shoukat Afshar-Sterle, Anita Kumari, Kevin Schmid, Christine Dijkstra, Chantelle Inguanti, Simone Ostrouska, Jordan Wilcox, Maxine Smith, Pavitha Parathan, Amr Allam, Hai-Hui Xue, Gabrielle T. Belz, John M. Mariadason, Andreas Behren, Grant R. Drummond, Roland Ruscher, David S. Williams, Bhupinder Pal, Wei Shi, Matthias Ernst, Dinesh Raghu, Lisa A. Mielke
Journal: Science Immunology (2023)

Intraepithelial lymphocytes (IELs), including αβ and γδ T cells (T-IELs), constantly survey and play a critical role in maintaining the gastrointestinal epithelium. We show that cytotoxic molecules important for defense against cancer were highly expressed by T-IELs in the small intestine. In contrast, abundance of colonic T-IELs was dependent on the microbiome and displayed higher expression of TCF-1/TCF7 and a reduced effector and cytotoxic profile, including low expression of granzymes. Targeted deletion of TCF-1 in γδ T-IELs induced a distinct effector profile and reduced colon tumor formation in mice. In addition, TCF-1 expression was significantly reduced in γδ T-IELs present in human colorectal cancers (CRCs) compared with normal healthy colon, which strongly correlated with an enhanced γδ T-IEL effector phenotype and improved patient survival. Our work identifies TCF-1 as a colon-specific T-IEL transcriptional regulator that could inform new immunotherapy strategies to treat CRC.
Immaturity of immune cells around the dural venous sinuses contributes to viral meningoencephalitis in neonates
Authors: Young-Chan Kim, Ji Hoon Ahn, Hokyung Jin, Myung Jin Yang, Seon Pyo Hong, Jin-Hui Yoon, Sang-Hoon Kim, Tirhas Niguse Gebre, Hyuek Jong Lee, You-Me Kim, Gou Young Koh
Journal: Science Immunology (2023)

High neonatal susceptibility to meningitis has been attributed to the anatomical barriers that act to protect the central nervous system (CNS) from infection being immature and not fully developed. However, the mechanisms by which pathogens breach CNS barriers are poorly understood. Using the Armstrong strain of lymphocytic choriomeningitis virus (LCMV) to study virus propagation into the CNS during systemic infection, we demonstrate that mortality in neonatal, but not adult, mice is high after infection. Virus propagated extensively from the perivenous sinus region of the dura mater to the leptomeninges, choroid plexus, and cerebral cortex. Although the structural barrier of CNS border tissues is comparable between neonates and adults, immunofluorescence staining and single-cell RNA sequencing analyses revealed that the neonatal dural immune cells are immature and predominantly composed of CD206hi macrophages, with major histocompatibility complex class II (MHCII)hi macrophages being rare. In adults, however, perivenous sinus immune cells were enriched in MHCIIhi macrophages that are specialized for producing antiviral molecules and chemokines compared with CD206hi macrophages and protected the CNS against systemic virus invasion. Our findings clarify how systemic pathogens enter the CNS through its border tissues and how the immune barrier at the perivenous sinus region of the dura blocks pathogen access to the CNS.
Low Mutation Load in a Supergene Underpinning Alternative Male Mating Strategies in Ruff (<i>Calidris pugnax</i>)
Authors: Jason Hill, Erik D Enbody, Huijuan Bi, Sangeet Lamichhaney, Weipan Lei, Juexin Chen, Chentao Wei, Yang Liu, Doreen Schwochow, Shady Younis, Fredrik Widemo, Leif Andersson
Journal: Molecular Biology and Evolution (2023)

A paradox in evolutionary biology is how supergenes can maintain high fitness despite reduced effective population size, the suppression of recombination, and the expected accumulation of mutational load. The ruff supergene involves 2 rare inversion haplotypes (satellite and faeder). These are recessive lethals but with dominant effects on male mating strategies, plumage, and body size. Sequence divergence to the wild-type (independent) haplotype indicates that the inversion could be as old as 4 million years. Here, we have constructed a highly contiguous genome assembly of the inversion region for both the independent and satellite haplotypes. Based on the new data, we estimate that the recombination event(s) creating the satellite haplotype occurred only about 70,000 yr ago. Contrary to expectations for supergenes, we find no substantial expansion of repeats and only a modest mutation load on the satellite and faeder haplotypes despite high sequence divergence to the non-inverted haplotype (1.46%). The essential centromere protein N (CENPN) gene is disrupted by the inversion and is as well conserved on the inversion haplotypes as on the noninversion haplotype. These results suggest that the inversion may be much younger than previously thought. The low mutation load, despite recessive lethality, may be explained by the introgression of the inversion from a now extinct lineage.